With the possible exception of teeth, tissues and organs of the body are capable of repairing injuries. An injury may be broadly defined as an interruption in the continuity of tissues, and these are repaired by reestablishing that continuity. Tissue repair is achieved primarily by proliferation, migration and differentiation of involved cells. Epithelial tissue heals chiefly by cellular migration, presumably because epithelium is essentially two-dimensional. With mesodermal tissues, however, the three-dimensional configuration is correlated with a somewhat different mode of repair that takes the form of an aggregate of cells that migrate into the lesion where they eventually redifferentiate into the tissue in question. These repair aggregates may take the form of granulation tissue in the case of dermis, fracture callus in the case of broken bones, or a comparable accumulation of cells between the cut ends of a severed tendon. (For a very brief review, see Cohen, I. K., et al., eds., Wound Healing, W. B. Saunders Co., Philadelphia, 1992, page 24).
The physiological process of wound healing or tissue repair has been arbitrarily divided into three major phases: the inflammatory phase, the proliferative phase, and the remodeling phase. A complex series of physiological and biochemical events can be correlated with macroscopic and microscopic changes in the wound as it heals.
The first, or inflammatory, phase of wound repair is initiated by a sequence of biochemical and cellular events that begins once the integrity and homeostasis of the tissue membranes are disrupted and involves both humoral and cellular components. A commonly observed feature of inflammation is the release of various eicosanoids and the appearance of polymophonuclear neutrophils, which migrate into both infected and noninfected wounds. The neutrophils are followed by monocytic macrophages that remove wound debris and contribute soluble mediators including additional eicosanoids that promote wound repair.
In infected wounds or in wounds with massive tissue destruction, the process of phagocytosis by both cell types is accompanied by a sequence of biochemical events that sharply increase oxygen uptake, producing a number of oxygen-derived free radicals including superoxide, hydroxyl and singlet oxygen, and derivative products such as hydrogen peroxide. These reactive products generate chemotactic factors for phagocytes and may be used by the phagocyte in destruction of infectious wound contaminants, but phagocyte-derived oxygen reduction products can also cause tissue damage and mediate ischemic injury (id., pages 302 to 303). Increased levels of inflammatory mediators, especially the vasoconstrictive ones, have been shown experimentally to enhance bacterial proliferation and microabscess formation. In infected wounds, this sets up a vicious cycle resulting in an imbalance of mediators normally useful in the repair process (id., pages 292 and 298).
In man, collagen plays a pivotal structural role in the proliferative and remodelling phases of wound healing and tissue repair (id., pages 146 to 147). The collagenous scaffold of the extracellular matrix comprises at least 13 genetically distinct types of collagen (ibid.), and the role the types play in the pathophysiology of tissue repair and their interplay with noncollagenous matrix materials is incompletely understood, especially the more recently described collagen types VI to XIII. In general, however, it has been observed that connective tissue reaction to injury eventually leads to the appearance of increased numbers of fibroblasts and finally to the accumulation of numerous rather large fibrils derived from type I collagen molecules. Fiber-rich scar tissue that ultimately forms contains fibrils predominantly derived from this type of collagen (ibid.). Investigators who have described the fibrillar components involved in wound healing of other tissues have observed type I collagen deposition in fracture healing of bone, both types I and III collagen deposition in the dermis, and type II in cartilage (ibid.). Type IV collagen forms a meshlike scaffold in basement membranes and type V collagen appears to be involved in the migration and movement of capillary endothelial cells during angiogenesis (ibid.).
In a study of controlled epithelial repair in guinea pigs, it was reported that collagen deposition in artificially infected incisions was inhibited by treatment with an acidified chlorite solution (Kenyon, A. J., et al., Am. Jo Vet Res. 47:96-101 (1986)). Treated wounds consistently epithelialized rapidly and seldom gaped or exhibited desquamated wound edges, but in the course of healing exhibited less wound breaking strength than control wounds. In the same study, treatment had an antimicrobial effect against Staphylococcus aureus experimentally introduced into the wounds.
The overall union of the opposing surfaces of a wound results in an adhering or uniting process referred to as an adhesion. The adhesion may involve tissue formation without differentiation of new elements, resulting in scarring and/or unnatural tissue associations. In surgery, foreign body reactions to lint and starch, serosal damage due to handling, ischemia and tension imposed by suturing and handling, and impaired fibrinolysis can contribute to adhesion formation. Fibrovascular adhesions complicate gynecological, intestinal, tendon, and cardiac surgery (Cohen, et al., cited above, page 576), and may result in ischemia. Adhesion prevention after surgical procedures has been attempted by reducing fibrin deposition using heparin and fibrinolytic agents, inhibiting fibroblast proliferation and collagen deposition using antihistamines or steroids, using careful surgical techniques and separating organs using various techniques, including separation with resorbable fabric. These methods have met with limited success due to the multiple and poorly understood etiology of adhesion formation (ibid.).
In past years, the management of wound treatment and repair was directed to wound healing after surgery or physical trauma. However, certain procedures currently employed in medicine such as those involving indwelling catheters for cleansing or administration of drugs necessitate the routine maintenance of what amount to infection-free wounds. For example, in the treatment of irreversible renal failure (briefly reviewed in Wyngaarden, J. B., et al., Cecil's Textbook of Medicine, 19th ed., Harcourt Brace Jovanovich, Philadelphia, 1992, pages 541 to 545), continuous ambulatory or cycling peritoneal dialysis (respectively called C.A.P.D. and C.C.P.D.) are now employed as an alternative to, or an adjunct with, hemodialysis or kidney transplantation. Each year, approximately 1.3 in 10,000 people in the United States develop end-stage renal disease, which is characterized by the accumulation of solutes in the body that can be removed by dialysis, diffusion across a semipermeable membrane down a chemical concentration. Peritoneal dialysis allows for the clearance of larger, and sometimes more toxic, substances than hemodialysis because of the greater permeability of the peritoneal membrane to larger molecules and the longer duration of treatment. Peritoneal dialysis is the dialysis treatment of choice for diabetics and patients with peripheral vascular disease or congestive heart failure because the method provides less cardiovascular stress than hemodialysis, and for children, because they have relatively good peritoneal clearance. Peritoneal dialysis also allows for greater freedom and schedule flexibility and is thus often preferred by working or disabled patients.
In peritoneal dialysis, the dialyzing solution is introduced into and removed from the peritoneal cavity through an abdominal incision. C.A.P.D. makes use of the fact that small molecular weight solutes reach complete equilibration with peritoneal fluid in 4 to 6 hours. Typically, a patient on C.A.P.D. exchanges 1.5 to 3.0 liters of sterile dialysate containing hypertonic glucose and physiologic electrolytes three to five times a day, introduced and removed through a peritoneal dialysis catheter. C.C.P.D. is becoming increasingly popular because the number of daily connects is reduced from four to two by employing the cycler during sleep and a single prolonged, C.A.P.D.-type daytime exchange. Many patients have been managed successfully with peritoneal dialysis for 5 to 10 years, but long-term technique failure rates remain higher than for chronic hemodialysis, mainly because of problems with the peritoneal catheter or recurrent peritonitis (ibid.).
One method almost universally employed for treating wounds of all types, including those surrounding indwelling catheters, is simple cleansing. Surgeons commonly employ mechanical forces to rid wounds of bacteria and other particulate matter retained on wound surfaces. Irrigation can rid wounds of large foreign bodies, but high pressure irrigation is necessary to remove smaller ones, and these can damage tissue and imbed foreign bodies in exposed tissue. Antibiotics added to surgical irrigation solutions appear to provide no additional benefit over saline alone (Hau, T., and Nishikawa, R., Surg. Gyn. & Obstet. 156:25-30 (1983)). Disinfectants added to the solutions are potentially toxic; many disinfectants that can be employed on unbroken skin cause tissue damage and damage to tissue defenses when employed on wounds, especially surgical wounds (Cohen, et al., cited above, pages 584-586). Exposure of blood to either Hibiclens.RTM. or Betadine.RTM. surgical scrub solutions, for example, damage its cellular components. Some surgical irrigants employ a surfactant such as Poloxamer 188 which does not produce discernible toxic effects or allergic reactions in tissues, but this has the disadvantage of exhibiting no antibacterial activity. For wounds that are prone to infection, systemic antibiotic treatment must be employed (ibid.).
It would be advantageous to have a quick-acting, broad-spectrum antimicrobial for use as a surgical irrigant or catheter and wound cleanser that rapidly degrades and does not irritate tissues. It would be especially advantageous to have an antimicrobial that not only does not interfere with wound healing, but, through interaction with the complex processes involved, actually promotes wound healing through a more beneficial route by minimizing scar and adhesion formation.